Compositions and methods for treating alzheimer's disease

Abstract

Provided herein are compositions and methods that improve cognition in individuals having or at risk of having Alzheimers disease, including familial Alzheimers disease, early-onset Alzheimers disease, and middle to late stage Alzheimers disease.

What is claimed is: 
     
         1 . A method of treating, preventing or delaying onset of an Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject a composition comprising ETP69 wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease; or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. 
     
     
         2 . The method of  claim 1 , wherein the familial Alzheimer's disease comprises Alzheimer's disease type 1. 
     
     
         3 . The method of  claim 1 , wherein the familial Alzheimer's disease comprises Alzheimer's disease type 3. 
     
     
         4 . The method of  claim 1 , wherein the familial Alzheimer's disease comprises Alzheimer's disease type 4. 
     
     
         5 . The method of  claim 1 , wherein the at least one mutation associated with familial Alzheimer's disease comprises a mutation in an amyloid precursor protein (APP) gene, a presenilin-1 (PSEN1) gene, or a presenilin-2 (PSEN2) gene. 
     
     
         6 . The method of  claim 5 , wherein the mutation in the APP gene codes for a mutation in the amyloid precursor protein amino acid sequence that is expressed from the APP gene. 
     
     
         7 . The method of  claim 6 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at valine 717 according to SEQ ID NO: 1. 
     
     
         8 . The method of  claim 7 , wherein the valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). 
     
     
         9 . The method of  claim 6 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises mutations at positions lysine 670 and methionine 671 according to SEQ ID NO: 1. 
     
     
         10 . The method of  claim 9 , wherein the lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670/671NL). 
     
     
         11 . The method of  claim 6 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at glutamate 693 according to SEQ ID NO: 1. 
     
     
         12 . The method of  claim 6 , wherein the mutation in the APP gene codes for a deletion at position glutamate 693 of the amyloid precursor protein amino acid. 
     
     
         13 . The method of  claim 11 , wherein the glutamate 693 of the of the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). 
     
     
         14 . The method of  claim 6 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at threonine 714 according to SEQ ID NO: 1. 
     
     
         15 . The method of  claim 14 , wherein the threonine 714 of the of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). 
     
     
         16 . The method of  claim 6 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at valine 715 according to SEQ ID NO: 1. 
     
     
         17 . The method of  claim 16 , wherein the valine 715 of the of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). 
     
     
         18 . The method of  claim 6 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at isoleucine 716 according to SEQ ID NO: 1. 
     
     
         19 . The method of  claim 18 , wherein the isoleucine 716 of the of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). 
     
     
         20 . The method of  claim 5 , wherein the mutation in the PSEN-1 gene codes for a mutation in the presenilin-1 amino acid sequence that is expressed from the PSEN-1 gene. 
     
     
         21 . The method of  claim 20 , wherein the mutation in the presenilin-1 amino acid sequence comprises a mutation at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 according to SEQ ID NO: 2. 
     
     
         22 . The method of  claim 21 , wherein the methionine 146 is mutated to leucine (M146L), the leucine 166 is mutated to proline (L166P), the isoleucine 213 is mutated to threonine (I213T), the arginine 278 is mutated to isoleucine (R278I), and the alanine 246 is mutated to glutamate (A246E). 
     
     
         23 . The method of  claim 2 , wherein the mutation in the PSEN-2 gene codes for a mutation in the presenilin-2 amino acid sequence that is expressed from the PSEN-2 gene. 
     
     
         24 . The method of  claim 23 , wherein the mutation in the presenilin-2 amino acid sequence comprises a mutation at asparagine 141 or methionine 239 according to SEQ ID NO: 3. 
     
     
         25 . The method of  claim 24 , wherein the asparagine 141 is mutated to isoleucine and the methionine 239 is mutated to valine. 
     
     
         26 . The method of  claim 1 , wherein the genetic risk factor associated with sporadic Alzheimer's disease comprises the subject being a carrier of an apolipoprotein (APOE) e4 allele. 
     
     
         27 . The method of  claim 1 , wherein the genetic risk factor associated with sporadic Alzheimer's disease comprises a mutation in a gene. 
     
     
         28 . The method of  claim 27 , wherein the gene comprises ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5/DRB1, INPP5D, MEF2C, MS4A6A/MS4A4E, PICALM, PLD3, ACE, PTK2B, —SORL1, TREM2, or UNC5C. 
     
     
         29 . The method of  claim 1 , wherein the subject is asymptomatic of Alzheimer's disease. 
     
     
         30 . The method of any one of  claim 1 , wherein the subject is less than about 25, about 30, about 35, about 40, about 45, about 50, about, about 55, about 60, about 65, or about 70 years of age. 
     
     
         31 . The method of  claim 1 , wherein the delaying onset of Alzheimer's disease comprises a delay in onset of at least one symptom of Alzheimer's disease. 
     
     
         32 . The method of  claim 31 , wherein the delay in onset of at least on symptom is at least about 6 months, about 12 months, about 18 months, about 2 years, about 3 years, about 5 years, about 10 years, about 15 years, or about 20 years. 
     
     
         33 . The method of  claim 31 , wherein the symptom comprises memory loss, difficulty concentrating, difficulty completing familiar tasks, confusion with time or place, difficulty understanding visual images and spatial relationships, language difficulties, misplacing items, decreased or poor judgement, social withdrawal, and/or mood or personality changes. 
     
     
         34 . The method of  claim 1 , wherein the method improves memory loss, difficulty concentrating, difficulty completing familiar tasks, confusion with time or place, difficulty understanding visual images and spatial relationships, language difficulties, misplacing items, decreased or poor judgement, social withdrawal, and/or mood or personality changes in the subject. 
     
     
         35 . The method of  claim 34 , wherein the treatment results in improvement in a mental status test and/or a neuroimaging test. 
     
     
         36 . The method of  claim 35 , wherein the mental status test is a Mini-Mental State Exam (MMSE), a Mini-Cog test, a Cantab Mobile test, a Cognigram test, a Cognivue test, or a Cognision and Automated Neuropsychological Assessment Metrics (ANAM) test. 
     
     
         37 . The method of  claim 36 , wherein the improvement comprises an improved score relative to a score obtained prior to administration of the composition. 
     
     
         38 . The method of  claim 35 , wherein the neuroimaging test is a magnetic resonance imaging (MRI) or computed tomography (CT). 
     
     
         39 . The method of  claim 38 , wherein the improvement comprises reduced beta-amyloid deposits as compared to an amount of beta-amyloid deposits measured prior to administration of the composition. 
     
     
         40 . A method of improving cognition in a subject at risk of developing Alzheimer's disease, the method comprising administering to the subject a composition comprising ETP69 wherein the subject has (i) at least one mutation associated with familial Alzheimer's disease; or (ii) at least one genetic risk factor associated with sporadic Alzheimer's disease. 
     
     
         41 . The method of  claim 40 , wherein the familial Alzheimer's disease comprises Alzheimer's disease type 1. 
     
     
         42 . The method of  claim 40 , wherein the familial Alzheimer's disease comprises Alzheimer's disease type 3. 
     
     
         43 . The method of  claim 40 , wherein the familial Alzheimer's disease comprises Alzheimer's disease type 4. 
     
     
         44 . The method of  claim 40 , wherein the at least one mutation associated with familial Alzheimer's disease comprises a mutation in an amyloid precursor protein (APP) gene, a presenilin-1 (PSEN1) gene, or a presenilin-2 (PSEN2) gene. 
     
     
         45 . The method of  claim 44 , wherein the mutation in the APP gene codes for a mutation in the amyloid precursor protein amino acid sequence that is expressed from the APP gene. 
     
     
         46 . The method of  claim 45 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at valine 717 according to SEQ ID NO: 1. 
     
     
         47 . The method of  claim 46 , wherein the valine 717 of the amyloid precursor protein is mutated to isoleucine (V717I), phenylalanine (V717F), glycine (V717G), or leucine (V717L). 
     
     
         48 . The method of  claim 45 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises mutations at positions lysine 670 and methionine 671 according to SEQ ID NO: 1. 
     
     
         49 . The method of  claim 45 , wherein the lysine 670 and methionine 671 are mutated to asparagine and lysine, respectively (KM670/671NL). 
     
     
         50 . The method of  claim 45 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at glutamate 693 according to SEQ ID NO: 1. 
     
     
         51 . The method of  claim 45 , wherein the mutation in the APP gene codes for a deletion at position glutamate 693 of the amyloid precursor protein amino acid. 
     
     
         52 . The method of  claim 51 , wherein the glutamate 693 of the of the amyloid precursor protein is mutated to glutamine (E693Q), glycine (E693G), or lysine (E693K). 
     
     
         53 . The method of  claim 45 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at threonine 714 according to SEQ ID NO: 1. 
     
     
         54 . The method of  claim 53 , wherein the threonine 714 of the of the amyloid precursor protein is mutated to isoleucine (T714I) or alanine (T714A). 
     
     
         55 . The method of  claim 45 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at valine 715 according to SEQ ID NO: 1. 
     
     
         56 . The method of  claim 55 , wherein the valine 715 of the of the amyloid precursor protein is mutated to methionine (V715M) or alanine (V715A). 
     
     
         57 . The method of  claim 45 , wherein the mutation in the amyloid precursor protein amino acid sequence comprises a mutation at isoleucine 716 according to SEQ ID NO: 1. 
     
     
         58 . The method of  claim 57 , wherein the isoleucine 716 of the of the amyloid precursor protein is mutated to valine (I716V) or phenylalanine (I716F). 
     
     
         59 . The method of  claim 44 , wherein the mutation in the PSEN-1 gene codes for a mutation in the presenilin-1 amino acid sequence that is expressed from the PSEN-1 gene. 
     
     
         60 . The method of  claim 59 , wherein the mutation in the presenilin-1 amino acid sequence comprises a mutation at methionine 146, leucine 166, isoleucine 213, arginine 278, or alanine 246 according to SEQ ID NO: 2. 
     
     
         61 . The method of  claim 60 , wherein the methionine 146 is mutated to leucine (M146L), the leucine 166 is mutated to proline (L166P), the isoleucine 213 is mutated to threonine (I213T), the arginine 278 is mutated to isoleucine (R278I), and the alanine 246 is mutated to glutamate (A246E). 
     
     
         62 . The method of  claim 44 , wherein the mutation in the PSEN-2 gene codes for a mutation in the presenilin-2 amino acid sequence that is expressed from the PSEN-2 gene. 
     
     
         63 . The method of  claim 62 , wherein the mutation in the presenilin-2 amino acid sequence comprises a mutation at asparagine 141 or methionine 239 according to SEQ ID NO: 3. 
     
     
         64 . The method of  claim 63 , wherein the asparagine 141 is mutated to isoleucine and the methionine 239 is mutated to valine. 
     
     
         65 . The method of  claim 40 , wherein the genetic risk factor associated with sporadic Alzheimer's disease comprises the subject being a carrier of apolipoprotein (APOE) e4 allele. 
     
     
         66 . The method of  claim 40 , wherein the genetic risk factor associated with sporadic Alzheimer's disease comprises a mutation in a gene. 
     
     
         67 . The method of  claim 66 , wherein the gene comprises ABCA7, AKAP9, BIN1, CASS4, CD2AP, CD33, CLU, EPHA1, FERMT2, HLA-DRB5/DRB1, INPP5D, MEF2C, MS4A6A/MS4A4E, PICALM, PLD3, ACE, PTK2B, —SORL1, TREM2, or UNC5C. 
     
     
         68 . The method of  claim 40 , wherein the subject is asymptomatic of Alzheimer's disease. 
     
     
         69 . The method of  claim 40 , wherein the subject is less than about 25, about 30, about 35, about 40, about 45, about 50, about, about 55, about 60, about 65, or about 70 years of age. 
     
     
         70 . The method of  claim 40 , wherein the method improves memory loss, difficulty concentrating, difficulty completing familiar tasks, confusion with time or place, difficulty understanding visual images and spatial relationships, language difficulties, misplacing items, decreased or poor judgement, social withdrawal, and/or mood or personality changes in the subject. 
     
     
         71 . The method of  claim 70 , wherein the treatment results in improvement in a mental status test and/or a neuroimaging test. 
     
     
         72 . The method of  claim 71 , wherein the mental status test is a Mini-Mental State Exam (MMSE), a Mini-Cog test, a Cantab Mobile test, a Cognigram test, a Cognivue test, or a Cognision and Automated Neuropsychological Assessment Metrics (ANAM) test. 
     
     
         73 . The method of  claim 72 , wherein the improvement comprises an improved score relative to a score obtained prior to administration of the composition. 
     
     
         74 . The method of  claim 71 , wherein the neuroimaging test is a magnetic resonance imaging (MRI) or computed tomography (CT). 
     
     
         75 . The method of  claim 74 , wherein the improvement comprises reduced beta-amyloid deposits as compared to an amount of beta-amyloid deposits measured prior to administration of the composition. 
     
     
         76 . The method of  claim 1  or  40 , wherein the administration results in increased synaptic integrity in the subject as compared to a synaptic integrity measured prior to administration of the composition. 
     
     
         77 . The method of  claim 1  or  40 , wherein the administration results in increased dendritic spine density as compared to a dendritic spine density measured prior to administration of the composition.